The broad objectives of this proposal are to 1) evaluate the differential impact of long pentraxin-3 (PTX3) genetic variation systemically and locally in the lung on the development of primary graft dysfunction (PGD) after lung transplant~ 2) determine the impact of PTX3 gene expression, protein production, and complement activation on the development of PGD using causal mediator analysis~ 3) examine the effect of PTX3 genetic variation and early PTX3 production on the development of bronchiolitis obliterans (BOS), or chronic allograft rejection~ and 4) provide the applicant with the skills, knowledge, and experience required to become an independent investigator in patient oriented clinical research. PGD is common after lung transplantation, affecting up to 30% of all recipients, and leads to increased morbidity in the form of prolonged hospitalization and mechanical ventilation and poor physical and lung function, early death, and increased risk of BOS. PGD likely results primarily from severe ischemia-reperfusion injury at the time of allograft implantation. Innate immune responses are likely upregulated in this setting~ however, their mechanistic role and important differences between systemic and lung-specific responses remain poorly understood. We have published two studies demonstrating that both increased PTX3 plasma levels and common variants in the PTX3 gene are associated with increased risk of PGD. However, the mechanism for these associations is unclear. Preliminary evidence indicates that increased gene expression and complement activation play integral roles in this relationship. This proposal leverages existing infrastructure at the University of Pennsylvania to develop a well- phenotyped cohort to study the genes- to-function mechanism of association for PTX3 and PGD and BOS. This prospective cohort study will be used to evaluate the role played by PTX3 circulating monocyte and pulmonary macrophage gene expression, PTX3 protein concentrations, and complement activation as mediators in the causal pathway between the exposure, PTX3 genotype, and the outcome, PGD after lung transplantation. Through a rigorous training plan involving didactics in advanced statistical analysis and genetic epidemiology, mentoring from established clinical investigators, and in-depth research experience, the applicant will gain skills in cohort design and development, molecular laboratory techniques, causal pathway and longitudinal data analysis, and lung transplant outcomes epidemiology. In order to ensure the applicant reaches all benchmarks in research, publication and career development, he will have regular meetings with his primary mentor and his multidisciplinary mentorship team. In addition to his mentors, the candidate's environment will provide easy collaboration, accessible statistical database support services, and numerous core laboratory services to facilitate his research and training goals. This proposal will allow th applicant to make significant contributions to the field of lung transplant medicine, develop into an independent clinical investigator and prepare him for successful future R01-funded projects directed at the development of therapeutics for PGD tailored to innate immune genetic risk factors.